T-Cell Depletion Eliminates the Development of Cardiac Allograft Vasculopathy in Mice Rendered Tolerant by the Induction of Mixed Chimerism

Uehara, Shuichiro; Chase, Catharine M.; Colvin, Robert B.; Madsen, Joren C.; Russell, Paul

doi:10.1016/j.transproceed.2006.10.147

Cited by 12 publications

(8 citation statements)

References 10 publications

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“…Chronic allograft vasculopathy (CAV) remains the major factor limiting long-term survival of heart allografts in humans (1,2) despite advances therapy. Mechanistic studies in mouse heart allografts have demonstrated three distinct pathways to CAV: T cells with minor antigen mismatch (3,4), natural killer (NK) cells with parent to F1 grafts (5,6) and MHC antibody with adoptive transfer of donor specific antibody (DSA) (4,7,8). Antibody-mediated CAV was demonstrated initially by adoptive transfer of polyclonal or monoclonal DSA in normal and immunodeficient recipients of heart allografts (8) and in human vascular allografts in mice (9).…”

Section: Introductionmentioning

confidence: 99%

A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and Alloantibody

Hirohashi

Chase

Pelle

et al. 2012

American Journal of Transplantation

210

163

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Chronic allograft vasculopathy (CAV) in murine heart allografts can be elicited by adoptive transfer of donor specific antibody (DSA) to class I MHC antigens and is independent of complement. Here we address the mechanism by which DSA causes CAV. B6.RAG1−/− or B6.RAG1−/−C3−/− (H-2b) mice received B10.BR (H-2k) heart allografts and repeated doses of IgG2a, IgG1 or F(ab’)2 fragments of IgG2a DSA (anti-H-2k). Intact DSA regularly elicited markedly stenotic CAV in recipients over 28 days. In contrast, depletion of NK cells with anti-NK1.1 reduced significantly DSA-induced CAV, as judged morphometrically. Recipients genetically deficient in mature NK cells (γ-chain knock out) also showed decreased severity of DSA-induced CAV. Direct NK reactivity to the graft was not necessary. F(ab’)2 DSA fragments, even at doses twofold higher than intact DSA, were inactive. Graft microvascular endothelial cells responded to DSA in vivo by increased expression of phospho-extracellular signal-regulated kinase (pERK), a response not elicited by F(ab’)2 DSA. We conclude that antibody mediates CAV through NK cells, by an Fc dependent manner. This new pathway adds to the possible mechanisms of chronic rejection and may relate to the recently described C4d-negative chronic antibody-mediated rejection in humans.

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Section: Introductionmentioning

confidence: 99%

A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and Alloantibody

Hirohashi

Chase

Pelle

et al. 2012

American Journal of Transplantation

210

163

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“…However, conflicting findings have been obtained in two studies, implying that deletion of recipient T cells specific for allogeneic MHC molecules on donor APCs (i.e., direct allorecognition) may not be sufficient to maintain allograft tolerance in macrochimeric mice. Uehara et al reported that skin and heart allografts accepted by mice displaying stable mixed chimerism later developed cardiac allograft vasculopathy (chronic rejection) dependent on the presence of host CD4 + T cells [24]. More recently, Shinoda et al found that depleting Foxp3 + T cells abrogated tolerance of skin and heart allografts in stable mixed chimeras without an associated loss of mixed chimerism [25].…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance

Granados

Bénichou

Kawai

2015

Current Opinion in Organ Transplantation

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Purpose of review This review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent findings Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Summary Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, as well as to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications.

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“…Clinically, chronic cardiac allograft rejection involves predominantly vascular damage with or without parenchymal fibrosis (51,52). CAV appears to have components of humoral, cellular, and NK cell-mediated mechanisms (1,53). After pruning of alloreactive CD4 ϩ T cells while there was chronic fibrosis with some cellular infiltration, there was minimal CAV.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Cardiac Allograft Survival across an MHC Mismatch after “Pruning” of Alloreactive CD4 T Cells

Watson

Zhang

et al. 2008

The Journal of Immunology

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Specific tolerance to allografts has been achieved by a variety of means. We have previously shown that ex vivo removal of dividing CD4+ T cells from an MLR or “pruning” delays skin allograft rejection. We tested pruning of alloreactive T cells as a strategy for retaining a broad T cell repertoire while removing alloreactive T cells in a model of cardiac allograft transplant. Using CFSE staining of responder BALB/c cells with stimulator C57BL/6 cells in an MLR, SCID mice were reconstituted with either dividing (D) or nondividing (ND) CD4+ T cells derived from an MLR and then challenged with heterotopic cardiac allografts. Mice reconstituted with D CD4+ T cells rejected cardiac allografts from the stimulator strain with a median survival time (MST) of 29 days, while mice reconstituted with ND CD4+ T cells maintained allografts from the stimulator strain (MST of >100 days) while rejecting third-party allografts (B10.BR) (MST = 11 days). ELISPOT assays demonstrate donor-specific hyporesponsiveness of the ND CD4+ T cells. TCR β-chain V region (TRBV) repertoire analysis demonstrates clonal expansion within both rejecting D cardiac allografts and ND cardiac allografts surviving for the long-term. Histology showed greater allograft infiltration by the D CD4+ T cells. The surviving ND cardiac allografts demonstrated reduced cellular infiltration and reduced incidence of allograft vasculopathy, but with the development of chronic fibrosis. Thus, pruning of alloreactive T cells allows long-term-specific cardiac allograft survival while retaining the ability to reject third-party allografts.

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T-Cell Depletion Eliminates the Development of Cardiac Allograft Vasculopathy in Mice Rendered Tolerant by the Induction of Mixed Chimerism

Cited by 12 publications

References 10 publications

A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and Alloantibody

A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and Alloantibody

Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance

Long-Term Cardiac Allograft Survival across an MHC Mismatch after “Pruning” of Alloreactive CD4 T Cells

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